The genetics of Parkinson’s disease: review of current and emerging candidates (original) (raw)

Advances in the genetics of Parkinson's disease

Acta Pharmacologica Sinica, 2008

Parkinson's disease (PD) is a neurodegenerative disorder affecting a significant proportion of the ageing population. The etiology is unknown and it is likely due to a multifactorial interaction of genes and the environment on the background of ageing. Findings in the last decade suggest that the contribution of genetics to familial forms of PD is much greater than previously appreciated. Twelve loci are now associated with highly penetrant autosomal dominant or recessive PD, and causative mutations have been identified in eight genes with mutation carriers often characterized by a phenotype indistinguishable from idiopathic disease. To date, PD pharmacotherapy is symptomatic only and does not slow disease progression. Understanding how genetic mutations cause familial PD is likely to clarify molecular mechanisms underlying PD in general and will provide a guide for the development of novel therapies, both preventative and palliative, applicable to all forms of parkinsonism. This review outlines the advances in the study of the genetic background of PD and their possible clinical implications.

Genetic contributions to Parkinson's disease

Sporadic Parkinson's disease (PD) is a common neurodegenerative disorder, characterized by the loss of midbrain dopamine neurons and Lewy body inclusions. It is thought to result from a complex interaction between multiple predisposing genes and environmental influences, although these interactions are still poorly understood. Several causative genes have been identified in different families. Mutations in two genes [a-synuclein and nuclear receptor-related 1 (Nurr1)] cause the same pathology, and a third locus on chromosome 2 also causes this pathology. Other familial PD mutations have identified genes involved in the ubiquitin – proteasome system [parkin and ubiquitin C-terminal hydroxylase L1 (UCHL1)], although such cases do not produce Lewy bodies. These studies highlight critical cellular proteins and mechanisms for dopamine neuron survival as disrupted in Parkinson's disease. Understanding the genetic variations impacting on dopamine neurons may illuminate other molecular mechanisms involved. Additional candidate genes involved in dopamine cell survival, dopamine synthesis, metabolism and function, energy supply, oxidative stress, and cellular detoxification have been indicated by transgenic animal models and/or screened in human populations with differing results. Genetic variation in genes known to produce different patterns and types of neurodegeneration that may impact on the function of dopamine neurons are also reviewed. These studies suggest that environment and genetic background are likely to have a significant influence on susceptibility to Parkinson's disease. The identification of multiple genes predisposing to Parkinson's disease will assist in determining the cellular pathway/s leading to the neurodegeneration observed in this disease.

Genetics of Parkinson's disease: the yield

Parkinsonism & Related Disorders, 2014

The discovery of genes implicated in familial forms of Parkinson's disease (PD) has provided new insights into the molecular events leading to neurodegeneration. Clinically, patients with genetically determined PD can be difficult to distinguish from those with sporadic PD. Monogenic causes include autosomal dominantly (SNCA, LRRK2, VPS35, EIF4G1) as well as recessively (PARK2, PINK1, DJ-1) inherited mutations. Additional recessive forms of parkinsonism present with atypical signs, including very early disease onset, dystonia, dementia and pyramidal signs. New techniques in the search for phenotype-associated genes (next-generation sequencing, genome-wide association studies) have expanded the spectrum of both monogenic PD and variants that alter risk to develop PD. Examples of risk genes include the two lysosomal enzyme coding genes GBA and SMPD1, which are associated with a 5-fold and 9-fold increased risk of PD, respectively. It is hoped that further knowledge of the genetic makeup of PD will allow designing treatments that alter the course of the disease.

Parkinson's disease: the genetics of a heterogeneous disorder

European Journal of Neurology, 2006

Since the first description of Parkinson's disease (PD) in 1817 attempts have been made to resolve the etiology of this common neurodegenerative disorder. In the last century the influence of heredity in PD was controversial. The identification of mutations in six genes responsible for Mendelian forms of PD; a-synuclein (SNCA), parkin (PRKN), ubiquitin C-terminal hydrolase L1 (UCH-L1), oncogene DJ-1, PTENinduced putative kinase 1 (PINK1), and most recently leucine-rich repeat kinase 2 (LRRK2), has confirmed the role of genetics in familial forms of the disease. The exact relationship of these familial disorders and related genes to the more common sporadic form is currently uncertain. The identification of LRRK2 mutations and the association of common variants in SNCA and UCH-L1 in apparently sporadic lateonset disease indicate these genes may be of greater importance than previously believed. The protein products of the six genes are involved in different pathways of neurodegeneration and have opened new avenues of research. This focused research will lead to the development of novel targeted therapies, which may revolutionize the treatment of PD for a substantial proportion of patients.

Molecular pathogenesis of Parkinson's disease: update

Journal of Neurology, Neurosurgery & Psychiatry, 2012

Parkinson disease (PD) is a neurodegenerative disease characterised by progressive disturbances in motor, autonomic and psychiatric functions. Much has been learnt since the disease entity was established in 1817. Although there are well established treatments that can alleviate the symptoms of PD, a pressing need exists to improve our understanding of the pathogenesis to enable development of disease modifying treatments. Ten responsible genes for PD have been identified and recent progress in molecular research on the protein functions of the genes provides new insights into the pathogenesis of hereditary as well as sporadic PD. Also, genome wide association studies, a powerful approach to identify weak effects of common genetic variants in common diseases, have identified a number of new possible PD associated genes, including PD genes previously detected. However, there is still much to learn about the interactions of the gene products, and important insights may come from chemical and genetic screens. In this review, an overview is provided of the molecular pathogenesis and genetics of PD, focusing particularly on the functions of the PD related gene products with marked research progress.

Parkinson's Disease: From Genetics to Clinical Practice

Current Genomics, 2014

Breakthroughs in genetics over the last decade have radically advanced our understanding of the etiological basis of Parkinson's disease (PD). Although much research remains to be done, the main genetic causes of this neurodegenerative disorder are now partially unraveled, allowing us to feel more confident that our knowledge about the genetic architecture of PD will continue to increase exponentially. How and when these discoveries will be introduced into general clinical practice, however, remains uncertain. In this review, we provide a general summary of the progress in the genetics of PD and discuss how this knowledge will contribute to the diagnosis and clinical management of patients with, or at risk of this disorder.

Identification of sixteen novel candidate genes for late onset Parkinson’s disease

Molecular Neurodegeneration

Background Parkinson’s disease (PD) is a neurodegenerative movement disorder affecting 1–5% of the general population for which neither effective cure nor early diagnostic tools are available that could tackle the pathology in the early phase. Here we report a multi-stage procedure to identify candidate genes likely involved in the etiopathogenesis of PD. Methods The study includes a discovery stage based on the analysis of whole exome data from 26 dominant late onset PD families, a validation analysis performed on 1542 independent PD patients and 706 controls from different cohorts and the assessment of polygenic variants load in the Italian cohort (394 unrelated patients and 203 controls). Results Family-based approach identified 28 disrupting variants in 26 candidate genes for PD including PARK2, PINK1, DJ-1(PARK7), LRRK2, HTRA2, FBXO7, EIF4G1, DNAJC6, DNAJC13, SNCAIP, AIMP2, CHMP1A, GIPC1, HMOX2, HSPA8, IMMT, KIF21B, KIF24, MAN2C1, RHOT2, SLC25A39, SPTBN1, TMEM175, TOMM22, TVP23...

Genetics of familial Parkinson's disease

Aristotle University Medical Journal, 2007

Parkinson’s disease (PD) is a complex, heterogenous neurodegenerative disorder. In the last century, the genetic contribution to the risk of PD was controversial. Recently, the identification of mutations in a-synuclein (SNCA), parkin (PARK2), ubiquitin C-terminal hydrolase L1 (UCHL1), PTEN-induced kinase 1 (PINK1), DJ-1, nuclear receptorrelated 1 (Nurr1) and leucine-rich repeat kinase 2 (LRRK2) genes has confirmed the role of genetics in familial forms of PD. These genetic findings have greatly advanced our knowledge on the pathophysiological background of familial PD. In addition to these genes, several other loci have been implicated in PD, although the responsible genes have not been identified, yet. Possible interactions between various already known or new candidate genes and the influence of environmental agents on the expression of PD-linked genes are in the scrutiny of recent genetic studies.